P1130: ACALABRUTINIB IN TREATMENT-NAIVE OR RELAPSED/REFRACTORY WALDENSTRÖM MACROGLOBULINEMIA: 5-YEAR FOLLOW-UP OF A PHASE 2, SINGLE-ARM STUDY
Authors: R. Owen, H. McCarthy, S. Rule, S. D’Sa, S. Thomas, O. Tournilhac, F. Forconi, M. José Kersten, P. Luigi Zinzani, S. Iyengar, J. Kothari, M. Minnema, E. Kastritis, B. Cheson, H. Walter, D. Greewald, R. Calvo, C.-C. Wun, R. Furman
Journal: HemaSphere (2022)

Background: Bruton tyrosine kinase (BTK) inhibitors are effective in the treatment of Waldenström macroglobulinemia (WM). Acalabrutinib is a highly selective, potent, covalent BTK inhibitor that demonstrated less toxicity and improved tolerability in a head-to-head trial versus ibrutinib in chronic lymphocytic leukemia. Aims: The aim of this trial was to determine the efficacy and safety of acalabrutinib in patients with treatment-naive (TN) or relapsed/refractory (R/R) WM. Interim results at 25 months (mo) of median follow-up have been previously reported. At a 5-year median follow-up, we report the final results of this trial. Methods: In this single-arm, multicenter, phase 2 trial, after informed consent was obtained, patients with TN or R/R WM received 100 mg oral acalabrutinib twice daily (or 200 mg acalabrutinib once daily, later switched to 100 mg twice daily). The primary endpoint was investigator-assessed overall response rate (ORR). Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Efficacy parameters were based on the modified 3rd International Workshop on Waldenström Macroglobulinemia (IWWM) criteria (Kimby 2006). Mutation data were available for a minority of patients and therefore are not reported. Results: Of 106 patients treated with acalabrutinib, 14 were TN and 92 were R/R; median age was 69 years (range 39–90); 94% had ECOG PS ≤1; median serum IgM was 3615 mg/dL (range 291–9740). Patients with R/R disease had a median of 2 prior therapies (range 1–7). ORR was 93% (95% CI: 66, 100) in the TN cohort and 95% (88, 98) in the R/R cohort; major response rates (≥partial response) were 79% (49, 95) and 82% (72, 89), respectively. Median DOR was not estimable (NE) (12, NE) in the TN cohort and 65 mo (55, NE) in the R/R cohort; the estimated 66-mo DOR was 90% (TN; 47, 99) and 45% (R/R; 27, 61). At a 63.7-mo median follow-up, median PFS rate was NE (TN; 19, NE) and 68 mo (R/R; 53, NE); estimated 66-mo PFS rate was 84% (TN; 48, 96) and 52% (R/R; 39, 63). Median OS rate was NE for the TN and R/R cohorts; estimated 66-mo OS rate was 91% (TN; 51, 99) and 71% (R/R; 60, 80). Of the patients who remained on treatment, 7 (50%) were in the TN cohort and 43 (47%) were in the R/R cohort. The main reasons for discontinuing acalabrutinib were adverse events (AEs) (4 [29%] patients in the TN cohort, 15 [16%] patients in the R/R cohort) and progressive disease (PD) (1 [7%] patient in the TN cohort, 20 [22%] patients in the R/R cohort). The most common AEs and selected events of clinical interest are listed in the Table. There were 12 grade 5 AEs (11 and 1 patients in the R/R and TN cohorts, respectively); 1 (intracranial hematoma [R/R]) was considered treatment-related. Image:Summary/Conclusion: Acalabrutinib is a highly effective treatment that achieved durable responses with a favorable safety profile in patients with TN or R/R WM.